This application focuses on an important endothelial cell tyrosine kinase receptor, Tie-2 and its downstream effectors. Tie-2 is essential for embryonic development and null embryos fail to properly assemble blood vessels. Recent investigations show that blocking Tie-2 ligand binding impairs tumor angiogenesis. We show preliminary data to suggest that the kinase function of this receptor is critical for tumor angiogenesis and that downstream pathways that may mediate this function include Akt signaling and thrombospondin expression. The goal of this application is to further explore the relationship between the Tie-2 kinase activity, its downstream effectors, and mammary tumor vascularization. Aim 1: Determine the function of Tie-2 kinase function in the angiogenesis and vasculogenesis of mammary tumors and metastases. Aim 2: Investigate whether Thrombospondins, Akt signaling, or both, mediate Tie-2 regulation of mammary tumor angiogenesis or vasculogenesis.